Abstract 5450: CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients

Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 410-769, Republic of Korea.
British Journal of Cancer (Impact Factor: 4.84). 03/2011; 104(7):1126-34. DOI: 10.1038/bjc.2011.24
Source: PubMed


We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin.
Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487).
Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death.
Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

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Available from: Soo-Jeong Cho, Feb 12, 2015
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    • "Tumor responses were evaluated using WHO criteria or RECIST criteria. Response rate was confirmed in three studies [11], [16], [17] and not confirmed in the rest of the studies. Clinical investigators were blind to the results of genotyping in only two studies [10], [13] and in the remaining eleven studies this information was not reported. "
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    ABSTRACT: Many reports have shown inconsistent results on the relationship between single nucleotide polymorphisms (SNPs) of X-ray repair cross complementing protein (XRCC1) gene and platinum-based chemotherapeutic efficacy. This meta-analysis aimed to summarize published data about the association between two SNPs of XRCC1 (Arg194Trp and Arg399Gln) and treatment outcomes of patients with advanced gastric cancer. We retrieved the relevant articles from MEDLINE, Web of Knowledge, and the China National Knowledge Infrastructure (CNKI) databases. Studies were selected according to specific inclusion and exclusion criteria. Study quality was assessed according to the guidelines outlined by Hayden, et al. and PRISMA guidelines. We estimated the odds ratio (OR) for response rate versus no response after platinum-based chemotherapy. Progression-free survival (PFS) and overall survival (OS) were evaluated by pooled Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs). We found that none of the XRCC1 Arg194Trp and Arg399Gln polymorphisms was significantly associated with tumor response. Stratified analysis by ethnicity or sensitivity analysis also showed that XRCC1 SNPs were not related with chemotherapy response. Patients with minor variant A allele were likely to have poorer 2-year survival rate than those with G/G genotype. However, in the group of 5-year follow up, there was no significant association between the A allele and OS yet. There is no evidence to support the use of XRCC1 Arg194Trp and Arg399Gln polymorphisms as prognostic predictors of TR and PFS in gastric patients treated with platinum-based chemotherapy. The relationship between minor variant A allele and OS requires further verification.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "This may reflect the fact that the variant alleles are linked to decreased conversion of tegafur, the active component of S-1, to 5-FU; this might have resulted in reduced exposure to the active metabolite of 5-FU. These results agree with those of previous studies on S-1- containing chemotherapies for gastric cancer, which showed that patients with CYP2A6 wild type have improved efficacy outcomes (Kong et al, 2009; Park et al, 2011a). "
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    ABSTRACT: Background: S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin. Methods: Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m−2 followed by oxaliplatin 85 mg m−2 on day 1 and S-1 80 mg m−2 per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed. Results: Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4–81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60. Conclusion: The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.
    Full-text · Article · Aug 2013 · British Journal of Cancer
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    • "Five studies (587 patients) evaluated the association between ERCC1 polymorphism and OS [18,20,22,26,30], but the studies by Park et al. and Stocker et al. could not be used for meta-analysis, which reported no significant association was observed between ERCC1 polymorphism and OS [18,20]. Therefore 3 Asian studies (301 patients) were used for combined analysis [22,26,30]. "
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    ABSTRACT: Background Despite genetic polymorphism in response to platinum/5-Fu chemotherapy in gastric cancer (GC) has been studied, data reported so far are conflicting and critical consideration is needed before translation to the treatment of GC. Methods We performed a meta-analysis by using 20 eligible studies to examine polymorphisms of ERCC1, GSTs, TS and MTHFR in predicting clinical outcomes (response rate, overall survival and toxicity) of GC patients treated with platinum/5-Fu-based chemotherapy. The association was measured using random/fixed effect odds ratios (ORs) or hazard ratios (HRs) combined with their 95% confidence intervals (CIs) according to the studies’ heterogeneity. Statistical analysis was performed with the software STATA 9.0 package. Results No significant association was found between response rate and genetic polymorphism in TS, MTHFR, ERCC1, GSTM1 and GSTP1. However, response rate was higher in GSTT1 (+) genotype compared with GSTT1 (−) genotype (T-/T+: OR=0.67, 95% CI: 0.47–0.97). With regard to long term outcomes, we could observe a significant longer overall survival in TS 3R/3R [(2R2R+2R3R)/3R3R: HR=1.29, 95% CI: 1.02–1.64] and GSTP1 GG/GA [(GG+AG)/AA: HR=0.51, 95% CI: (0.39, 0.67)] genotypes. In addition, significant association was demonstrated between toxicity and genetic polymorphism in TS, MTHFR and GSTP1 in included studies. Conclusion Polymorphisms of ERCC1, GSTs, TS and MTHFR were closely associated with clinical outcomes of GC patients treated with platinum/5-Fu-based chemotherapy. Studies with large sample size using the method of multi-variant analyses may help us to give more persuasive data on the putative association in future.
    Full-text · Article · Sep 2012 · BMC Gastroenterology
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